Protein kinases are important in the transmission of biochemical signals, which initiate cell replication. Protein kinases are enzymes that catalyze the transfer of a phosphate group from ATP to an amino acid residue, such as tyrosine, serine, threonine, or histidine on a protein. Regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration. Specific protein kinases have been implicated in adverse conditions including cancer [Traxler, P. M., Exp. Opin. Ther. Patents, 8, 1599 (1998); Bridges, A. J., Emerging Drugs, 3, 279 (1998)], restenosis [Mattsson, E., Trends Cardiovas. Med. 5, 200 (1995); Shaw, Trends Pharmacol. Sci. 16, 401 (1995)], atherosclerosis [Raines, E. W., Bioessays, 18, 271 (1996)], angiogenesis [Shawver, L. K., Drug Discovery Today, 2, 50 (1997); Folkman, J., Nature Medicine, 1, 27 (1995)] and osteoporosis [Boyce, J. Clin. Invest., 90,1622 (1992)]. Compounds capable of inhibiting the activity of receptor tyrosine kinases are knwn to be useful in the treatment of cancers, including but not limited to for example, non-small cell lung cancer (NSCLC), breast cancer, polycystic kidney disease, colonic polyps, and stroke in mammals.
Specific kinase inhibitors include compounds such as (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2- enamide (neratinib); 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile (bosutinib); N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (sunitinib); 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide (imatinib); 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide (sorafinib); N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib); 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide (nilotinib); N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine (laratinib); and others. Many kinase inhibitors are known to possess anti-tumor activity and are therefore useful for treating certain disease states, such as cancer, that result, at least in part, from deregulation of this receptor.
The kinase inhibitor neratinib is a weak base having low bioavailability and low solubility in both water and alcohol. Certain tablet formulations of neratinib, including the maleate salt form of neratinib, provide a limited amount of active (<40 weight percent) that can be loaded in the oral dosage form. It would be desirable to provide a formulation of neratinib maleate for oral administration that allowed larger amounts of active (>40 weight percent) in the oral dosage form.
Notably, diarrhea and nausea, often severe, are associated with existing oral formulations of kinase inhibitors such as tablet and capsule formulations of neratinib. Such oral formulations prepared by conventional methods have been used and are currently being used clinical trials of neratinib and have been associated with severe emesisi and diarrhea in those clinical trials. See, e.g., A Phase I Study with Neratinib (HKI-272), an Irreversible Pan ErbB Receptor Tyrosine Kinase Inhibitor, in Patients with Solid Tumors, Wong et al., Clinical Cancer Research Apr. 1, 2009 15, 2552. Similar side effects have been noted in connection with oral formulations of other kinase inhibitors. It would therefore be very desirable to provide formulations of neratinib and other kinase inhibitors for oral administration that reduces or eliminates side effects of emesis and diarrhea.